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Schizophrenia - Genetic factors
Substantial evidence suggests that the diagnosis of schizophrenia has a heritable component (some estimates are as high as 80%). Current research suggests that environmental factors play a significant role in the expression of any genetic disposition towards schizophrenia (i.e. if someone has the genes that increase risk, this will not automatically result in a diagnosis of schizophrenia later in life). However, while the study of schizophrenia genetics has confirmed the importance of genes in etiology, it has not been possible to definitively identify the specific DNA variants, protein alterations or biological processes underlying this association. In search of evidence for the genetic link researchers have adopted a number of strategies: Twin studies A recent review of the genetic evidence from twin studies has suggested a more than 28% chance of one identical twin obtaining the diagnosis if the other already has itTorrey, E.F., Bowler, A.E., Taylor, E.H. & Gottesman, I. I (1994) Schizophrenia and manic depressive disorder. New York: Basic books. ISBN 0-465-07285-2 (see twin studies), but such studies are not noted for pondering the likelihood of similarities of social class and/or other socio-psychological factors between the twins. Studies of adopted children reared apart Adoption studies support the genetic theory of transmission. In 1994, Kety et al looked at schizophrenia in the biological and adoptive relatives of schizophrenic adoptees, and compared this to a demographically matched group of control adoptees Kety SS, Wender PH, Jacobsen B, Ingaham LJ, Jansson L, Faber B, Kinney DK. Mental illness in the biological and adoptive relatives of schizophrenic adoptees. Archives of General Psychiatry 1994 June; 51: 442-455. In the sample of adoptees with chronic schizophrenia, the disorder was matched only in their biological relatives and not their adoptive relatives. The prevalence of the disorder was 10 times higher in the biological relatives of the schizophrenic adoptees than in the biological relatives of the control group. Molecular genetics There is currently a great deal of effort being put into molecular genetic studies of schizophrenia, which attempt to identify specific genes which may increase risk. Because of this, the genes that are thought to be most involved can change as new evidence is gathered. A 2003 review of linkage studies listed seven genes as likely to increase risk for a later diagnosis of the disorder. C. Lewis, D. Levinson, L. Wise, L. DeLisi, R. Straub, I. Hovatta, N. Williams, S. Schwab, A. Pulver, S. Faraone (2003)Genome Scan Meta-Analysis of Schizophrenia and Bipolar Disorder, Part II: Schizophrenia in The American Journal of Human Genetics, Volume 73, Issue 1, pp34-48 Two more recent reviews Owen, M.J., Craddock, N. & O'Donovan, M.c. (2005)'Schizophrenia:Genes at Last?' in Trends in Genetics, Volume 21, Issue 9, pp518-525 Riley B, Kendler KS (2006) Molecular genetic studies of schizophrenia. Eur J Hum Genet, 14 (6), 669-80. have suggested that the evidence is currently strongest for two genes known as dysbindin (DTNBP1) and neuregulin (NRG1), with a number of other genes (such as COMT, RGS4, PPP3CC, ZDHHC8, DISC1, and AKT1) showing some early promising results that have not yet been fully replicated. Modes of Transmission These different methods all suggest that since the concordance rate among MZ twins is about 48% Gottesman, I. I. (1991)'Schizophrenia Genesis: The Origins of Madness', New York: Freeman. and people can carry the genotype for schizophrenia without developing the condition. However, such individuals are at risk of a higher incidence of neurological, motor, planning, attentional, social and memory dysfunctions. Erlenmeyer-Kimling, L. (2000). 'Neurobehavioral Deficits in Offspring of Schizophrenic Parents: Liability Indicators and Predictors of Illness' in the American Journal of Medical Genetics, vol 97 (1), pp65-71 Therefore there is probably not a single dominant gene for schizophrenia. A number of mechanisms have been suggested: Single gene model with incomplete penetrance Penetrance is a term used in genetics that describes the extent to which the properties controlled by a gene, its phenotype, will be expressed. A highly penetrant gene will express itself almost regardless of the effects of environment, whereas a gene with low penetrance will only sometimes produce the symptom or trait with which it has been associated. In some cases, the phenotype in question will occur only when the gene is present; in other cases, they may occur for unrelated reasons. In the case of low penetrance it is difficult to distinguish environmental from genetic factors. Penetrance and heritability appear closely related at first glance, but in fact it is possible to carry a huge number of inherited genes with low penetrance and not be aware of them. The opposite is not the case however, if you carry a higher penetrant gene, you will know (assuming the gene has a noticeable effect, many do notneeded). Polygenic model Another model of transmission is the polygenic model which assumes inheritance of a phenotypic characteristic (trait) that is attributable to two or more genes and their interaction with the environment. Unlike monogenic traits, polygenic traits do not follow patterns of Mendelian inheritance (qualitative traits). Instead, their phenotypes typically vary along a continuous gradient depicted by a bell curve. This model is appealing because it could explain why concordance in twins increases with severity of illness and why the risk of schizophrenia increases with the number of relatives affected. Risch and Baron (1984) concluded that either of these models model fitted with the analysis of family data and were consistent with the additional observations observations of lifetime incidence, mating-type distribution, and monozygotic twin concordance. For the polygenic model, they estimated components of variance to be: *polygenes 81.9%; *common sib environment 6.9% *random environment 11.2%. For the mixed model they postulated that the single locus is more likely to be recessive than dominant, with a high frequency and low penetrance. For the most likely recessive mixed model the variance was partitioned as follows: *major locus, 62.9%; *polygenes, 19.5%; *common sib environment, 6.6%; *random environment, 11%. ----- See also References & Bibliography Key texts Books Papers *Erlenmeyer-Kimling, L. (2000). "Neurobehavioral Deficits in Offspring of Schizophrenic Parents: Liability Indicators and Predictors of Illness." American Journal of Medical Genetics 97(1):65–71. *Marshall, J.R. (1984) The genetics of schizophrenia revisited, Bulletin of the British Psychological Society 37: 177-81. *Risch, N.; Baron, M. (1984).Segregation analysis of schizophrenia and related disorders. Am. J. Hum. Genet. 36: 1039-1059, PMID 6496472 Full text Additional material Books Papers *Google Scholar External links http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=181500 OHIM schizophrenia page] Category:Schizophrenia - Genetic factors [[Category:Schizophrenia